title: Targeting ERBB receptors shifts their partners and triggers persistent ERK signaling through a novel ERBB/EFNB1 complex.
abstract: Most squamous cell carcinomas of the head and neck (HNSCC) overexpress ERBB1/EGFR, but EGF receptor (EGFR)-targeted therapies have yielded disappointing clinical results in treatment of this cancer. Here, we describe a novel interaction between EGFR and the ligand EphrinB1 (EFNB1), and we show that EFNB1 phosphorylation and downstream signaling persists in the presence of cetuximab. Mechanistically, cetuximab drives a shift in EGFR dimerization partners within the signaling complex, suggesting that targeted drugs may trigger partner rearrangements that allow persistent pathway activation. EFNB1 attenuation slowed tumor growth and increased survival in a murine model of HNSCC, suggesting a substantial contribution of EFNB1 signaling to HNSCC development. Together, our findings suggest that EFNB1 is part of the EGFR signaling complex and may mediate drug resistance in HNSCC as well as other solid tumors.
authors.affiliation: Authors' Affiliation: Cancer Biology Research Center, Sanford Research, University of South Dakota, Sioux Falls, South Dakota.
authors.forename: Paola D
authors.initials: PD
authors.lastname: Vermeer
authors.forename: Paul L
authors.initials: PL
authors.lastname: Colbert
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Wieking
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Vermeer
authors.forename: John H
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D036387:Ephrin-B1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D036387:Ephrin-B1; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D018719:Erb-b2 Receptor Tyrosine Kinases; C484288:EFNB1 protein, human; C508053:ERBB2 protein, human; C535150:MAPK1 protein, human; C516742:PTPN13 protein, human